Nucleotide sequences coding for a mammalian coltage-gated potassium channel protein, the amino acid encoded by the nucleic acid and use thereof

ABSTRACT

The present invention relates to the mammalian KCNA7 gene coding for a voltage-gated potassium channel protein. The invention further relates to methods for identifying agents capable of modulating voltage-gated potassium ion channel activity. Blockers of the KCNA7 ion channel would be expected i.a. to increase insulin release and thereby reduce hyperglycemia associated with non-insulin-dependent diabetes mellitus

TECHNICAL FIELD

[0001] The present invention relates to novel nucleic acid molecules coding for a mammalian voltage-gated potassium channel protein. The invention firer relates to methods for identifying agents capable of modulating voltage-gated potassium ion channel activity.

BACKGROUND ART

[0002] Voltage-gated potassium ion channels (Kv channels), the largest sub-family of the ion channel superfamily, play important roles in a wide variety of cells (for reviews see Choe. S. et al. (1999) Trends Biochem. Sci. 24: 345-349; Lehmann-Hom, F. & Jurkat-Wottn K. (1999) Physiological Reviews 79; 1317-1372). From repolarizing membranes in response to action potentials, to regulating hormone secretion and calcium signaling, the potassium channels are critical genes for controlling the interactions of cells with their environments. Membrane depolarization activates voltage-gated potassium channels that, once opened, conduct potassium ions along the concentration gradient against the electric field. This outward current leads to repolarization of the membrane.

[0003] Kv channels in mammalian cells are encoded by an extended family of at least nineteen genes. The largest subfamily, Kv1, is related to the fly Shaker gene and contains at least seven members, Kv1.1-Kv1.7. The mammalian voltage-gated Shaker-related potassium-channel gene Kv1.7 (Kalman K. et al. (1998) J. Biol. Chem. 273; 5851-5857; see also U.S. Pat. No. 5.559,009) has been mapped to mouse chromosome 7 and human chromosome 19q 13.3. a region that has been suggested to contain a diabetic susceptibility locus.

[0004] Kv ion channels are in part responsible for the maintenance of cellular electrical activity. An imbalance in electrical activity is thought to be an underlying cause, at least in part, of several psychiatric diseases including schizophrenia, depression, anxiety, epilepsy, and neurodegenerative disorders (Herdon H. (1996) Potassium channel modulators and the central nervous system in Potassium channels and their modulators. Ed Evans J M. Hamilton T C, Longman S D, Stemp G. Taylor and Francis, Inc. pp. 361-383.) Thus compounds which maintain the electrical activity of the cell, would be expected to alleviate the symptoms of such diseases.

[0005] Therefore, ion channels may be useful targets for discovering ligands or drugs to treat many diverse disorders and defects, including schizophrenia, depression, anxiety, attention deficit hyperactivity disorder, migraine, stroke, ischemia, and neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, glaucoma and macular degeneration. In addition compounds which modulate ion channels can be used for the treatment of cardiovascular diseases including ischemia, congestive heart failure, arrhythmia high blood pressure and restenosis.

[0006] Roe et al. (1996) J. Biol. Chem. 271:32241, demonstrated a correlation between channel blockade with the non-specific blockers tetraethylammonium and 4-aminopyridine and an increase in insulin release. Since voltage-gated potassium channels modulate insulin secretion from pancreatic β-cells, selective blockers of the new potassium ion channel would be expected to increase insulin release and thereby reduce hyperglycemia associated with non-insulin-dependent diabetes mellitus

[0007] An ongoing effort to create a physical framework for the human genome using NotI restriction sites has generated a large number of sequences preferentially containing exons (Kashuba V. I. et al. (1999) Gene 239: 259-271; Zabarovsky, E. R. et al. (2000) Nucleic Acids Research 239: 259-271). As NotI sites are preferentially detected in CpG (methylation-free) islands (Kashuba, V. I. et al., supra), and as most CpG islands include the 5-end of genes (Bird, A. (1987) Trends in Genetics 3(12): 342-347), the identification of sequences flanking NotI sites can aid in the identification of the edges of genes. This preference for regions adjoining or within genes has resulted in the discovery of a number of new genes.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008]FIG. 1

[0009] The KCNA7 gene. (A) Genomic structure of KCNA7, including a putative promoter and the exon positions. (B) Computational detection of potential skeletal muscle regulatory regions (boxes marked “Unknown TF”, cf. positions 105 to 114 and 201 to 211 in SEQ ID NO:13) in human KCNA7 gene and putative mouse sequence. Potential Sp1 and Mef2 binding sites are also shown (cf. positions 151 to 159 and 183 to 192 in SEQ ID NO:13).

[0010]FIG. 2 Alignment of the deduced amino acid sequence of KCNA7 with murine Kcna7. Black and gray boxes indicate identical and similar amino acid residues, respectively. (A) Alignment of N-termini of the human KCNA7 and murine Kcna7 (accession numbers AF032099 and NM_(—)010596.1). (B) Alignment of the human KCNA7 and murine Kcna7 proteins suggested after the introduction of an additional nucleotide G in the position 362 of the Kcna7 sequence (Accession no. NM_(—)010596.1).

[0011]FIG. 3 Hybridization of the KCNA7 to a Human Multiple Tissue Northern blot

DESCRIPTION OF THE INVENTION

[0012] The present invention is directed to a novel, putative member of the mammalian voltage-gated potassium channel protein family, the potassium channel KCNA7. We report the cloning of the human ortholog to the murine Kv1.7 potassium ion channel, the tissue distribution of its expression, and the analysis of the genomic sequence encoding the gene.

[0013] The maximal open reading frame in the human gene encodes a protein of 456 amino acids (SEQ ID NO:2). The predicted product exhibits 91% amino acid identity to the murine voltage-gated potassium channel Kv1.7 (Kcna7SEQ ID NO; 6), which plays an important role in the repolarization of cell membranes. Based on the high similarity, the human protein has been classified as the ortholog of the mouse gene and designated KCNA7. A structural prediction identified a pore region characteristic of potassium channels and a transmembrane segment of the cyclic nucleotide gated channel. Northern expression analysis revealed the gene is expressed preferentially in skeletal muscle and heart. A single mRNA isoform was observed, with a size of approximately 4 kb. Using fluorescence in situ hybridization, the gene was mapped to chromosomal band 19q13.3. A genomic c sequence was identified in the database from this region, and the KCNA7 gene structure determined. Computational analysis of the genomic sequence reveals the location of a putative promoter and a likely muscle-specific regulatory region.

[0014] Further, a murine kcna7 gene sequence has been identified, which is different from the previously published murine sequence.

[0015] Consequently, in a first aspect this invention provides an isolated nucleic acid molecule selected from:

[0016] (a) nucleic acid molecules comprising a nucleotide sequence as shown in SEQ ID NO:1 or 11,

[0017] (b) nucleic acid molecules comprising a nucleotide sequence capable of hybridizing, under stringent hybridization conditions, to a nucleotide sequence complementary the polypeptide coding region of a nucleic acid molecule as defined in (a) and which codes for a biologically active KCNA7 polypeptide or a functionally equivalent modified form thereof; and

[0018] (c) nucleic acid molecules comprising a nucleic acid sequence which is degenerate as a result of the genetic code to a nucleotide sequence as defined in (a) or (b) and which codes for a KCNA7 polypeptide or a functionally equivalent modified form thereof.

[0019] The term “stringent hybridization conditions” is known in the art from standard protocols (e. Ausubel et at., supra) and could be understood as eg hybridization to filter-bound DNA in 0 5 M NaHPO₄, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at +65° C. and washing in 0.1×SSC/0.1 % SDS at +68° C.

[0020] The nucleic acid molecules according to the present invention includes cDNA, chemically synthesized DNA, DNA isolated by PCR, genomic DNA, and combinations thereof RNA transcribed from DNA is also encompassed by the present invention.

[0021] In a preferred form of the invention, the said nucleic acid molecule has a nucleotide sequence identical with SEQ ID NOS: 1 or 11 of the Sequence Listing. However, the nucleic acid molecule according to the invention is not to be limited strictly to the sequence shown as SEQ ID NO:1 or 11. Rather the invention encompasses nucleic acid molecules carrying modifications like substitutions, small deletions, insertions or inversions, which nevertheless encode proteins having substantially the biochemical activity of the mammalian KCNA7 polypeptide according to the invention. Included in the invention are consequently nucleic acid molecules, the nucleotide sequence of which is at least 90% homologous, preferably at least 95% homologous, with the nucleotide sequence shown as SEQ ID NO:1 or 11 in the Sequence Listing.

[0022] Included in the invention is also a nucleic acid molecule which nucleotide sequence is degenerate because of the genetic code, to the nucleotide sequence shown as SEQ ID NO:1 or 11. A sequential grouping of three nucleotides, a “codon”, codes for one amino acid Since there are 64 possible codons, but only 20 natural amino acids, most amino no acids are coded for by more than one codon. This natural “degeneracy”, or “redundancy”, of the genetic code is well known in the art. It will thus be appreciated that the nucleotide sequence shown in the Sequence Listing is only an example within a large but definite group of sequences which will encode the mammalian KCNA7 polypeptide

[0023] The invention also provides an isolated polypeptide encoded by the nucleic acid according to claim 1. In a preferred form, the said polypeptide has an amino acid sequence according to SEQ ID NO:2 or 12 of the Sequence Listing. However, the polypeptide according to the invention is not to be limited strictly to a polypeptide with an amino acid sequence identical with SEQ ID NO:2 or 12 in the Sequence Listing. Rather the invention encompasses polypeptides carrying modifications like substitutions, small deletions, insertions or inversions, which polypeptides nevertheless have substantially the biological activities of mammalian KCNA7.

[0024] In another aspect, the invention provides a vector harboring the nucleic acid molecule as defined above. The term “vector” refers to any carrier of exogenous DNA that is useful for transferring the DNA to a host cell for replication and/or appropriate expression of the exogenous DNA by the host cell. The said vector can e.g. be a replicable expression vector, which carries and is capable of mediating the expression of a DNA molecule according to the invention. In the present context the term “replicable” means that the vector is able to replicate in a given type of host cell into which is has been introduced. Examples of vectors are viruses such as bacteriophages, cosmids, plasmids and other recombination vectors. Nucleic acid molecules are inserted into vector genomes by methods well known in the art.

[0025] Included in the invention is also a cultured host cell harboring a vector according to the invention. Such a host cell can be a prokaryotic cell, a unicellular eukaryotic cell or a cell derived from a multicellular organism The host cell can thus e.g. be a bacterial cell such as an E. Coli cell; a cell from yeast such as Saccharomyces cervisiac or Pichia pastoris, or a mammalian cell. The methods employed to effect introduction of the vector into the host cell are standard methods well known to a person familiar with recombinant DNA methods. A further aspect of the invention is a process for production of a mammalian KCNA7 polypeptide which comprises culturing a host cell as defined above under conditions whereby said polypeptide is produced, and recovering said polypeptide.

[0026] In yet an important aspect, this invention provides a method for identifying an agent capable of modulating voltage-gated potassium ion channel activity, comprising

[0027] (i) providing a cell expressing the mammalian KCNA7 polypeptide;

[0028] (ii) contacting said cell with a candidate agent; and

[0029] (iii) monitoring said cell for an effect that is not present in the absence of said candidate agent As used herein, the term “agent” means a biological or chemical compound such as a simple or complex organic molecule, a peptide, a protein or an oligonucleotide.

[0030] Specifically, such a method can comprise the steps (i) contacting a candidate agent with a nucleic acid molecule according to the invention, or with the encoded mammalian KCNA7 polypeptide; and (ii) determining whether said candidate agent modulates the expression of the said nucleic acid molecule, or whether the candidate agent modulates the biological activities of the said polypeptide. In this context, the term “biological activities” is intended to encompass triggering release or uptake of protein or non-protein molecules from the cell, or triggering the opening of the channels and the movement of ions across the cellular membrane, and the electrical signal which accompanies the passage of the ions across the membrane as assessed with the technique of electrophysiology. For example, activity can be determined by measuring ion flux. As used herein, the term “ion flux” includes ion current. Activity can also be measured by measuring changes ink membrane potential using electrodes or voltage-sensitive dyes, or by measuring neuronal or cellular activity such as action potential duration or frequency, the threshold for stimulating action potentials, long-term potentiation or long-term inhibition. For references, see e.g. “Electroplhysiology, A Practical Approach”, D I Wallis (ed.), IRL Press at Oxford University Press, 1993; or “Voltage and patch Clamping wit Microelectrodes”, T G Smith, H Lecar, S T Redman and P W Gage (eds), Waverly Press, Inc for the American Physiology Society, 1985.

[0031] Blockers of the mammalian KCNA7 ion channel would be expected to increase insulin release and thereby reduce hyperglycemia associated with non-insulin-dependent diabetes mellitus. Consequently, agents modulating the mammalian KCNA7 gene or KCNA7 protein could be useful for the treatment of diabetes and related medical conditions.

[0032] Further, modulators of the mammalian KCNA7 ion channel could be useful in the treatment of ion channel related problems such as schizophrenia, depression, anxiety, attention deficit hyperactivity disorder migraine, stroke, ischemia, glaucoma, macular degeneration, epilepsy, and neurodegenerative disease such as Alzheimer's disease and Parkinson's disease.

[0033] For screening purposes, appropriate host cells can be transformed with a vector having a reporter gene under the control of the KCNA7 gene according to this invention. The expression of the reporter gene can be measured in the presence or absence of an agent with known activity (i.e. a standard agent) or putative activity (i.e. a “test agent” or “candidate agent”). A change in the level of expression of the reporter gene in the presence of the candidate agent is compared with that effected by the standard agent. In this way, active agents are identified and their relative potency in this assay determined.

[0034] As used herein, the term “reporter gene” means a gene encoding a gene product that can be identified using simple, inexpensive methods or reagents and that can be operably linked to the KCNA7 gene or an active fragment thereof Reporter genes such as, for example, a luciferase, β-galactosidase, alkaline phosphatase, or green fluorescent protein reporter gene, can be used to determine transcriptional activity in screening assays according to the invention (see, for example, Goeddel (ed.), Methods Enzymol., Vol. 185, San Diego: Academic Press, Inc. (1990); see also Sambrook, supra).

[0035] The effect of candidate agents on the KCNA7 potassium channel can be monitored by methods known in the art. For instance, the rate of ⁸⁶Rb efflux from a ⁸⁶Rb loaded cell, expressing the mammalian KCNA7 ion channel, can be monitored (cf. Example 7, below). When the candidate agent is a polypeptide, its interaction with the KCNA7 polypeptide cat be monitored by well known methods for determination of protein-protein interactions. Examples of such methods, applicable for the soluble portion of KCNA7, are the yeast two-hybrid system and FRET (fluorescence resonance energy transfer) (cf. Examples 8 and 9, respectively). Another example is determination of changes in membrane potential using the FLIPR system (cf. Example 10)

[0036] In a further aspect, the invention provides a method for the identification of an agent modulating transcription of the human KCNA7 gene, said method comprising the steps

[0037] (i) contacting a candidate agent with a regulatory region shown as positions 102 to 246, or a part thereof, such as in particular positions105 to 114 or 201 to 211, in SEQ ID NO: 13. and

[0038] (ii) determining whether said candidate agent modulates expression of the human KCNA7 gene, such modulation being indicative for an agent modulating transcription of the human KCNA7 gene.

[0039] In a particular embodiment, the novel molecules identified by the screening methods according to the invention are low molecular weight organic molecules, in which case a composition or pharmaceutical composition can be prepared thereof for oral intake, such as in tablets. The compositions, or pharmaceutical compositions, comprising the nucleic acid molecules, vectors, polypeptides, antibodies and compounds identified by the screening methods described herein, can be prepared for any route of administration including but not limited to, oral, intravenous, cutaneous, subcutaneous, nasal, intramuscular or intraperitoneal. The nature of the carrier or other ingredients will depend on the specific route of administration and particular embodiment of the invention to be administered. Examples of techniques and protocols that are useful in this context air, inter alia, found in Remington's Pharmaceutical Sciences, 16^(th) edition, Osol, A. (ed.). 1980, which is incorporated herein by reference in its entirety.

[0040] The dosage of these low molecular weight compounds will depend on the disease state or condition to be treated and other clinical factors such as weight and condition of the human or animal and the route of administration of the compound. For treating human or animals, between approximately 0.5 mg/kg of body weight to 500 mg/kg of body weight of the compound can be administered. Therapy is typically administered at lower dosages and is continued until the desired therapeutic outcome is observed.

Materials and Methods

[0041] cDNA library from heart (Stratagene, La Jolla, Calif., USA) in λ ZAP II was used for the screening and isolation of cDNA clones. Marathon-Ready™ cDNA from skeletal muscle (Clontech, Palo Alto, Calif., USA) was used for 5′- and 3′-RACE PCR.

[0042] Homology searches were performed using BLASTX and BLASFN programs (Altscul et al. (1997) Nucleic Acids Res. 25:3389-3402; Gish & States (1993) Nature Genetics 3: 266-272) Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http://wwwncbi.nlm.nih.gov). A search for motifs common to protein families was performed with the Prosite motif library. Information about the Prosite motifs is available at the ISREC server (http//www.isrec.isb-sib.ch).

[0043] A prediction of membrane-spanning regions and their orientation was made. Software for the prediction of transmembrane regions is available through various sources, e.g. at http.//www ch. embnet org/software/TMPRED_form.html. Exon positions in the genomic sequence were determined with “est_genome” (http://www.sanger ac.uk), a specialized tool for the prediction of exon boundaries using ESTs (See Mott. R. (1997) Computer Applications in the Biosciences 13(4): 477-478). Promoter prediction was performed on the genomic sequence with the algorithm “PromoterInspector” (Scherf, M. et al. (2000) J. Mol. Biol. 297: 599-606). The positions of putative transcription regulatory regions for muscle-specific expression were determined with a logistic regression model (Wasserman, W. W. & Fickett, J. W. (1998) J. Mol. Biol. 278; 167-181).

[0044] Throughout this description the terms “standard methods” and “standard procedures”, when used in the context of molecular biology techniques, are to be understood as protocols and procedures found in an ordinary laboratory manual such as: Current Protocols in Molecular Biology, editors F. Ausubel et al., John Wiley and Sons, Inc. 1994, or Sambrook. J., Fritsch, E. F. and Maniatis, T., Molecular Cloning: A laboratory manual, 2nd Ed., Cold Spring Harbor Laboratory Press. Cold Spring Harbor, N.Y. 1989.

[0045] Additional features of the invention will be apparent from the following Examples. Examples 1 to 5 are actual, while Examples 6 to 10 are prophetic.

EXAMPLES OF THE INVENTION EXAMPLE 1 Identification of Human KCNA7

[0046] Construction of NotI linking libraries was described previously (Zabarovsky et al. (1994) Genomics 20: 312-316; Zabarovsky et al. (2000) Nucleic Acids Research 28: 1635-1639). The No/I linking clone NR1-253 (SEQ ID NO:3; GenBank Accession No. AQ939522. approximately 900 bp) displayed 85% identity over 658 nucleotides with the murine voltage-gated potassium channel Kv1.7 (Kcna7) (SEQ ID NO:4; GenBank Accession No. AF032099; Kalman, K. et al. (1998) J. Biol. Chem. 273: 5851-5857).

[0047] A set of overlapping human cDNA sequences was obtained via a combination of cDNA library, screening and RACE-PCR according to standard methods. The final full-length human sequence (4372 bp, SEQ ID NO:1) was obtained by the fusion of the longest 3′-and 5′-RACE PCR products with cDNA clone (p5kv1-7) containing the complete ORF. The KCNA7 nucleotide sequence encodes a deduced protein of 456 amino acids (SEQ ID NO:2)

[0048] Screening the genome sequence database revealed the KCNA7 gene in the draft sequence of the human BAC clone CTB-60B 18 (GenBank accession number AC008687.3; positions 84249-83339 and 82186-78726; reverse orientation). Like the murine ortholog, but unlike other human Kv1 channels genes, the human KCNA7 gene is split into taco exons of length 911 and 3461 bp, respectively (FIG. 1A; positions 1-911 and 912-4372 in SEQ ID NO 1). The human gene intron is 1153 bp in length, compared to the reported murine intron of length 1.9 kb (Kalman et al., supra).

[0049] The human KCNA7 protein (SEQ ID NO:2) displays high level of amino acid identity to the mouse Kcna7 protein (SEQ ID NO:6) (90% in 452 aa overlap, score 809 bits) and less similarity to a variety of human potassium channel genes (<71% in 411-434 aa overlap). In fact, in many extended regions the human and mouse genes are identical (FIG. 2). Based on the observed similarity, we postulate that the human and murine genes are true orthologs. Nucleic acid similarity is less profound, in the best cases reaching 82%-86%, which is consistent with the variability between orthologous human and rodent genes (Makalowski, W. & Boguski, M. S. (1998) Proc. Natl. Acad. Sci. of U.S.A. 95(16): 9407-9412).

[0050] The deduced human KCNA7 protein contains six putative membrane-spanning domains. The region between amino acids 237 and 448 is recognized as a transmembrane part of the cyclic nucleotide gated channel and contains a pore region amino acids 342-397). The protein contains conserved sites for various post-translational modifications. As other Shaker-related channels, KCNA7 has a potential tyrosine kinase phosphorylation site (RPSFDAVLY) in its N-terminal region (amino acids 62-70) (Chandy, K. G. & Gutman, G. A (1995) in Handbook of Receptors and Channels: Ligand and Voltage-gated Ion Channels North, A. ed.) pp.1-72, CRC Press, Boca Raton, Fla.). Two protein kinase C consensus sites. viz. TLR (amino acids 304-306) and SMR (amino acids 308-310) are present in the cytoplasmic loop; at least one of these sites is present in all members of the Kv1 family (Chandy & Gutman, supra).

Example 2 Identification of a Frameshift in the Published Murine cDNA Sequence

[0051] The human and murine cDNA sequences indicate different N-terminal sequences in the encoded polypeptides (FIG. 2A). Potassium channels can vary significantly at the 5′-ends but as these orthologous genes are highly similar, it seems more likely that a frameshift within the murine cDNA sequence could have produced an inaccurate N-terminal sequence.

[0052] Consistent with this hypothesis, the human cDNA sequence contains the sequence CGGC at positions 383-386, which corresponds to the sequence CGC at positions 523-525 in the murine cDNA sequence (SEQ ID NO:5). In support of this difference being a frameshift error, the murine ESTs for Kcna7 (Accession numbers AI1322534.1 (SEQ ID NO; 7) and A1324179 (SEQ ID NO:8)) contain the sequence CGGC Further, a murine genomic sequence (GenBank accession no. AC073711) for the Kcna7 gene, or possibly for a recently created paralog or pseudogene, contains the CGGC sequence. If the CGGC sequence is correct, the murine ORF would be altered at the N-terminal such that the first 88 amino acids of the published murine sequence would be replaced by 10 amino acids identical to the human N-terminal sequence. With this correction to the murine sequence, it would show 91% identity with the human sequence (FIG. 2B).

[0053] To directly check the sequence of murine Kcna7 gene we performed PCR with mouse genomic DNA and the PCR primers shown as SEQ ID NOS: 9 and 10. Sequencing of the PCR product, according to standard procedures, confirmed that the mouse gene comprises the CGGC sequence and therefore its N-terminal protein sequence is identical to the human. The corrected murine nucleotide and amino acid sequences are shown as SEQ ID NOS; 11 and 12, respectively.

Examples 3 Expression Analysis

[0054] Northern hybridization of the cloned human gene was carried out using a filter containing RNA from a variety of muscle tissues (Clontech, Human Muscle #7765-1). Northern expression analysis revealed the highest expression of KCNA7 in skeletal muscle and heart (FIG. 3). A single band of approximately 4 kb was observed. Skeletal muscle is believed to be the principal tissue responding to insulin to modify glucose levels in the body (see e.g. Zierath, J. R. et al (2000) Diabetologia 43:821-835). Expression in smooth muscles was detected at a lower level consistent with the expression of murine Kcna7.

Example 4 Identification of Putative Regulatory Regions

[0055] Analysis of the human genomic sequence suggestions the location of some regulatory control regions The “PromoterInspector” algorithm (Scherf, M. et at. (2000) J. Mol Biol 297. 599-606) suggested the presence of a single promoter adjacent to the identified first exon. A unique algorithm (see Wasserman, W. W. & Ficket:, J. W. (1998) J. Mol. Biol. 278: 167-181) for the identification of transcriptional regulatory regions directing skeletal muscle-specific transcription was applied to the KCNA7 genomic sequence. A putative regulatory region was identified at approximately −1100 relative to the 5′-end of the first exon (FIG. 1B; cf. positions 102 to 246 in SEQ ID NO:13. Potential binding sites for both Mef-2 and Sp-1 transcription factors (Wasserman & Fickett.,supra) were identified within this region.

Example 5 In situ Hybridization

[0056] Fluorescence in situ hybridization (FISH) analysis with metaphase chromosomes was performed a, described previously (Protopopov et al. (1996) Chromosome Research 4:443-447). The NotI linking clone NR1-253, to which the KCNA7 gene corresponds (see Example 1, above), was assigned to chromosomal band 19q 13.3. As previously observed (Kalman, K. et al. (1998) J. Biol. Chem. 273: 5851-5857), this map location is consistent with a putative diabetes susceptibility gene that has been suggested to be present al 19q 13.3 This suggestion is especially strong for Finnish families wit associated hypertension and difficulties ill insulin-stimulated glucose storage (Groop, L. C. et al (1993) New Engl. J. Medicine 328: 10-14; Lehto, M. et al. (1993) Genomics 15: 460-461 Elbein S. C. et al. (1994) Diabetes 43: 1061-1065). For the Kcna7 gene, expression in mouse pancreatic islet cells was demonstrated (Kalman et al., supra). Thus, human KCNA7 could be linked to the pathogenesis of type II diabetes mellitus, in some humans.

Example 6 Expression of Voltage-gated Ion Channel Polypeptides in Mammalian Cells

[0057] (a) Expression of Voltage-gated Ion Channel Polypeptides in 293 Cells

[0058] For expression of voltage-gated ion channel polypeptides in mammalian cells 293 (transformed human, primary embryonic kidney cells), a plasmid bearing the relevant voltage-gated ion channel coding sequence is prepared, using vector pCDNA6 (Invitrogen) Vector pCDNA6 contains the CMV promoter and a blasticidin resistant gene for selection of stable transfectants. Many other vectors can be used containing, for example, different promoters, epitope tags for detection and/or purification of the protein, and resistance genes. The forward primer for amplification of this voltage-gated ion channel polypeptide encoding cDNA is determined by procedures as well known in the art and preferably contains a 5′ extension of nucleotides to introduce the HindIII cloning site and nucleotides matching the voltage-gated ion channel nucleotide sequence. The reverse primer preferably contains a 5′ extension of nucleotides to introduce an XhoI restriction site for cloning and nucleotides corresponding to the reverse complement of the voltage-gated ion channel nucleotide sequence. The PCR conditions are 5° C. as the annealing temperature. The PCR product is gel purified and cloned into the HindIII-XhoI sites of the vector.

[0059] The DNA is purified using Qiagen chromatography columns and transfected into 293 cells using DOTAP transfection media (Boehringer Mannheim, Indianapolis, Ind.). Transiently n-transfected cells are tested for expression after 24 hours of transfection, using Western blots probed with anti-His and anti-voltage-gated ion channel peptide antibodies Permanently transfected cells are selected with Zeocin and propagated. Production of the recombinant protein is detected from both cells and media by western blots probed with anti-His, anti-Myc or anti-voltage-gated ion channel peptide antibodies.

[0060] (b) Expression of Voltage-gated Ion channel Polypeptides in COS Cells

[0061] For expression of voltage-gated ion channel polypeptides in COS7 cells, a polynucleotide molecule having a nucleotide sequence of SEQ ID NO:1 or complementary nucleotide sequences thereof, can be cloned into vector p3-CI. This vector is a pUC18-derived plasmid that contains the HCMV (human cytomegalovirus) promoter-intron located upstream from the bGH (bovine growth hormone) polyadenylation sequence and a multiple cloning site. In addition, the plasmid contains the dhrf (dihydrofolate reductase) gene which provides selection in the presence of the drug methotrexane (MTX) for selection of stable transformants. Many other vectors can be used containing, for example, different promoters, epitope tags for detection and/or purification of the protein, and resistance genes.

[0062] The forward primer is determined by procedures known in the art and preferably contains a 5′ extension which introduces an XbaI restriction site for cloning, followed by nucleotides which correspond to a nucleotide sequence given in SEQ ID NO:1, or portion thereof The reverse primer is also determined by methods well known in the art and preferably contains a 5′-extension of nucleotides which introduces a SalI cloning site followed by nucleotides which correspond to the reverse complement of a nucleotide sequence given in SEQ ID NO:1, or portion thereof.

[0063] The PCR consists of an initial denaturation step of 5 min at 95° C., 30 cycles of 30 sec denaturation at 95° C., 30 sec annealing at 58° C. and 30 sec extension at 72°C., followed by 5 min extension at 72° C. The PCR product is gel purified and ligated into the XbaI and SalI sites of vector p3-CI. This construct is transformed into E. coli cells for amplification and DNA purification. The DNA is purified with Qiagen chromatography columns and transfected into COS 7 cells using Lipofectamine reagent (Gibco/BRL), following the manufacturer's protocols. Forty-eight and 72 hours after transfection, the media and the cells are tested for recombinant protein expression.

[0064] Voltage-gated ion channel polypeptides expressed in cultured COS cells can be purified by disrupting cells via homogenization and purifying membranes by centrifugation, solubilizing the protein using a suitable detergent, and pawing the protein by, for example, chromatography. Purified voltage-gated ion channel is concentrated to about 0.5 mg/ml in an Amicon concentrator fitted with a YM-10 membrane and stored at fan −80° C.

Example 7 Use of Kv1.7 Expression Construct to Identify Kv1.7-specific Glucose-dependent Insulin Secretagogues

[0065] The KCNA7 expression construct [described above] can be used to generate functional potassium channels with unique properties. This construct can be used for expression of functional KCNA7 channels in mammalian cell lines that do not express endogenous potassium channels (e.g. CV-1, NTH-3T3, or RBL cell lines). These cell lines can then be loaded with ⁸⁶Rb (Rb ions permeate through potassium channels nearly as well as potassium ions) in the presence of absence of extrinsic materials, and KCNA7 modifiers identified by their ability to alter ⁸⁶Rb-efflux. When natural toxins are identified which block KCNA7 activity, modifiers of KCNA7 activity could also be identified by their ability to block or reverse the binding of labeled toxins to cells expressing this channel. Compounds discovered in either of these manners could then be formulated and administered as therapeutic agents for the treatment of NIDDM.

Example 8 Interaction Trap/Two-Hybrid System

[0066] In order to assay for voltage-gated ion channel polypeptide-interacting proteins, the interaction trap/two-hybrid library screening method can be used. This assay was first described in Fields & Song (1989) Nature 340: 245-246. A protocol is published in Current Protocols in Molecular Biology 1999, John Wiley & Sons. New York, and Ausubel, F. M. et al. 1992. Short Protocols in Molecular Biology, 4^(th) ed., Greene and Wiley-Interscience, NY. Kits are available from Clontech, Palo Alto, Calif. (Matchmaker Two-Hybrid System 3).

[0067] A fusion of the nucleotide sequences encoding an intracellular, soluble portion of the voltage-gated ion channel polypeptide and the yeast transcription factor GAL4 DNA-binding domain (DNA-BD) is constructed in an appropriate plasmid (i.e., pGBKT7), using standard subcloning techniques. Similarly, a GAL4 active domain (AD) fusion library is constructed in a second plasmid (i.e., pGADT7) from cDNA of potential voltage-gated ion channel polypeptide-binding proteins. The DNA-BD/voltage-gated ion channel fusion construct is verified by sequencing, and tested for autonomous reporter gene activation and cell toxicity, both of which would prevent a successful two-hybrid analysis. Similar controls are performed with the AD/library fusion construct to ensure expression in host cells and lack of transcriptional activity. Yeast cells are transformed (ca. 10⁵ transformants/mg DNA) with both the voltage-gated ion channel and library fusion plasmids according to standard procedures. In vivo binding of DNA-BD/voltage-gated ion channel with AD/library proteins results in transcription of specific yeast plasmid reporter genes (i.e., lacZ, HIS3, ADE2, LEU2). Yeast cells are plated on nutrient-deficient media to screen for expression of reporter genes. Colonies are dually assayed for β-galactosidase activity upon growth in Xgal (5-bromo-4-chloro-1-indolyl-β-D-galactoside) supplemented media (filter assay for β-galactosidase activity is described in Breeden, et al., Cold Spring Harb. Symp. Quant. Biol., 1985, 50, 643). Positive AD-library plasmids are rescued from transformants and reintroduced into the original yeast strain as well as other strains containing unrelated DNA-BD fusion proteins to confirm specific voltage-gated ion channel polypeptide/library protein interactions. Insert DNA is sequenced to verify the presence of an open reading frame fused to GAL4 AD and to determine the identity of the voltage-gated ion channel polypeptide-binding protein.

Example 9 FRET Analysis of Protein-Protein Interactions

[0068] In order to assay for voltage-gated ion channel polypeptide-interacting proteins, fluorescence resonance energy transfer (FRET) methods can be used. An example of this type Of assay is described in Mahajan, N. P. et al. (1998) Nature Biotechnology 16: 547-552. This assay is based on the fact that when two fluorescent moieties having the appropriate excitation/emission properties are brought into close proximity, the donor fluorophore, when excited, can transfer its energy to the acceptor fluorophore whose emission is measured. The emission spectrum of the donor must overlap with the absorption spectrum of the acceptor while overlaps between the two absorption spectra and between the two emission spectra, respectively, should be minimized. An example of a useful donor/acceptor pair is Cyan Fluorescent Protein (CFP)/Yellow Fluorescent Protein (YFP) (Tsien (1998) Annu. Rev. Biochem. 67, 509-544).

[0069] A fusion of the nucleotide sequences encoding an intracellular soluble portion of the voltage-gated ion channel polypeptide and CFP is constructed in an appropriate plasmid, using standard subcloning techniques. Similarly, a nucleotide encoding a YFP fusion of the possibly interacting target protein is constructed in a second plasmid The CFP/voltage-gated ion channel polypeptide fusion construct is verified by sequencing. Similar controls are performed with the YFP/target protein construct The expression of each protein can be monitored using fluorescence techniques (e.g., fluorescence microscopy or fluorescence spectroscopy). Host cells are transformed with both the CFP/voltage-gated ion channel polypeptide and YFP/target protein fusion plasmids according to standard procedure. In situ interactions between CFP/voltage-gated ion channel polypeptide and the YFP/target protein are detected by monitoring the YFP fluorescence after exciting the CFP fluorophore. The fluorescence is monitored using fluorescence microscopy or fluorescence spectroscopy. In addition, changes in the interaction due to e.g., external stimuli are measured using time-resolved fluorescence techniques.

[0070] Alternatively, a YFP fusion library may be constructed from cDNA of potential voltage-gated ion channel polypeptide-binding proteins Host cells are transformed with both the CFP/voltage-gated ion channel polypeptide and YFP fusion library plasmids. Clones exhibiting FRET are then isolated and the protein interacting with a voltage-gated ion channel polypeptide is identified by rescuing and sequencing the DNA encoding the YFP/target fusion protein.

Example 10 High Throughput Screening for Modulators of Ion Channels Using FLIPR

[0071] One method to identify compounds that modulate the activity of an ion channel polypeptide is through the use of the FLIPR (Fluorometric Imaging Plate Reader) system, which is developed to perform cell-based, high-throughput screening (HTS) assay s measuring, for example, membrane potential (For a review, see Schroeder K. S. and Neagle B. D. (1996) FLIPR: a new instrument for accurate, high throughput optical screening. J. Biomol. Screen. 1: 75-80). Changes in plasma membrane potential correlate with the modulation of ion channels, as ions move into or out of the cell The FLIPR system measures such changes in membrane potential. This is accomplished by loading cells expressing an ion channel gene with a cell-membrane permeable fluorescent indicator dye suitable for measuring changes in membrane potential such as diBAC (bis-(1,3-dibutylbarbituric acid)pentamethine oxonol, Molecular Probes). Thus the modulation of ion channel activity is assessed with FLIPR and detected as changes in the emission spectrum of the diBAC dye.

[0072] As an example, COS cells that have been transfected with an ion channel gene of Interest are bathed in diBAC. Due to the presence of both endogenous potassium channels in the cells as well as the transfected channel, the addition of 30 mM extracellular potassium causes a membrane depolarization This results in an increase in diBAC uptake by the cell, and thus an overall increase in fluorescence. When cells ale treated with a potassium channel opener, such as chromakalim, the membrane is hyperpolarized causing a net outflow of diBAC, and thus a reduction in fluorescence. In this manner the effect of unknown test compounds on membrane potential can be assessed using this assay.

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 13 <210> SEQ ID NO 1 <211> LENGTH: 4372 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (357)..(1727) <400> SEQUENCE: 1 aaacttggag agacgcagga caggatcccg gcggcagaag gacggagaga aaggggaccc 60 cgggacggga aaggcgcaga gcaggcgcgg gcggcggcgg cggcggggca gggcagggcg 120 ggcgtcccgg cagagggcgc gcggtcgccc tgtcgccctc cgccccgccg gggtcacagt 180 gccccctccc tcgcgcccta gccgccctgc cgggctattt ttacgcgcgg acaccggaca 240 ccggacaccg ggctggggcg gcggcggcgg cggccgaggc ggccgaggcg gggccgcacc 300 ggggccgggc gtcggggcca cacgtcggtt cgcgggtcgc cggggctgcg cgcgcc atg 359 Met 1 gag ccg cgg tgc ccg ccg ccg tgc ggc tgc tgc gag cgg ctg gtg ctc 407 Glu Pro Arg Cys Pro Pro Pro Cys Gly Cys Cys Glu Arg Leu Val Leu 5 10 15 aac gtg gcc ggg ctg cgc ttc gag acg cgg gcg cgc acg ctg ggc cgc 455 Asn Val Ala Gly Leu Arg Phe Glu Thr Arg Ala Arg Thr Leu Gly Arg 20 25 30 ttc ccg gac act ctg cta ggg gac cca gcg cgc cgc ggc cgc ttc tac 503 Phe Pro Asp Thr Leu Leu Gly Asp Pro Ala Arg Arg Gly Arg Phe Tyr 35 40 45 gac gac gcg cgc cgc gag tat ttc ttc gac cgg cac cgg ccc agc ttc 551 Asp Asp Ala Arg Arg Glu Tyr Phe Phe Asp Arg His Arg Pro Ser Phe 50 55 60 65 gac gcc gtg ctc tac tac tac cag tcc ggt ggg cgg ctg cgg cgg ccg 599 Asp Ala Val Leu Tyr Tyr Tyr Gln Ser Gly Gly Arg Leu Arg Arg Pro 70 75 80 gcg cac gtg ccg ctc gac gtc ttc ctg gaa gag gtg gcc ttc tac ggg 647 Ala His Val Pro Leu Asp Val Phe Leu Glu Glu Val Ala Phe Tyr Gly 85 90 95 ctg ggc gcg gcg gcc ctg gca cgc ctg cgc gag gac gag ggc tgc ccg 695 Leu Gly Ala Ala Ala Leu Ala Arg Leu Arg Glu Asp Glu Gly Cys Pro 100 105 110 gtg ccg ccc gag cgc ccc ctg ccc cgc cgc gcc ttc gcc cgc cag ctg 743 Val Pro Pro Glu Arg Pro Leu Pro Arg Arg Ala Phe Ala Arg Gln Leu 115 120 125 tgg ctg ctt ttc gag ttt ccc gag agc tct cag gcc gcg cgc gtg ctc 791 Trp Leu Leu Phe Glu Phe Pro Glu Ser Ser Gln Ala Ala Arg Val Leu 130 135 140 145 gcc gta gtc tcc gtg ctg gtc atc ctc gtc tcc atc gtc gtc ttc tgc 839 Ala Val Val Ser Val Leu Val Ile Leu Val Ser Ile Val Val Phe Cys 150 155 160 ctc gag acg ctg cct gac ttc cgc gac gac cgc gac ggc acg ggg ctt 887 Leu Glu Thr Leu Pro Asp Phe Arg Asp Asp Arg Asp Gly Thr Gly Leu 165 170 175 gct gct gca gcc gca gcc ggc ccg ttc ccc gct ccg ctg aat ggc tcc 935 Ala Ala Ala Ala Ala Ala Gly Pro Phe Pro Ala Pro Leu Asn Gly Ser 180 185 190 agc caa atg cct gga aat cca ccc cgc ctg ccc ttc aat gac ccg ttc 983 Ser Gln Met Pro Gly Asn Pro Pro Arg Leu Pro Phe Asn Asp Pro Phe 195 200 205 ttc gtg gtg gag acg ctg tgt att tgt tgg ttc tcc ttt gag ctg ctg 1031 Phe Val Val Glu Thr Leu Cys Ile Cys Trp Phe Ser Phe Glu Leu Leu 210 215 220 225 gta cgc ctc ctg gtc tgt cca agc aag gct atc ttc ttc aag aac gtg 1079 Val Arg Leu Leu Val Cys Pro Ser Lys Ala Ile Phe Phe Lys Asn Val 230 235 240 atg aac ctc atc gat ttt gtg gct atc ctt ccc tac ttt gtg gca ctg 1127 Met Asn Leu Ile Asp Phe Val Ala Ile Leu Pro Tyr Phe Val Ala Leu 245 250 255 ggc acc gag ctg gcc cgg cag cga ggg gtg ggc cag cag gcc atg tca 1175 Gly Thr Glu Leu Ala Arg Gln Arg Gly Val Gly Gln Gln Ala Met Ser 260 265 270 ctg gcc atc ctg aga gtc atc cga ttg gtg cgt gtc ttc cgc atc ttc 1223 Leu Ala Ile Leu Arg Val Ile Arg Leu Val Arg Val Phe Arg Ile Phe 275 280 285 aag ctg tcc cgg cac tca aag ggc ctg caa atc ttg ggc cag acg ctt 1271 Lys Leu Ser Arg His Ser Lys Gly Leu Gln Ile Leu Gly Gln Thr Leu 290 295 300 305 cgg gcc tcc atg cgt gag ctg ggc ctc ctc atc ttt ttc ctc ttc atc 1319 Arg Ala Ser Met Arg Glu Leu Gly Leu Leu Ile Phe Phe Leu Phe Ile 310 315 320 ggt gtg gtc ctc ttt tct agc gcc gtc tac ttt gcc gaa gtt gac cgg 1367 Gly Val Val Leu Phe Ser Ser Ala Val Tyr Phe Ala Glu Val Asp Arg 325 330 335 gtg gac tcc cat ttc act agc atc cct gag tcc ttc tgg tgg gcg gta 1415 Val Asp Ser His Phe Thr Ser Ile Pro Glu Ser Phe Trp Trp Ala Val 340 345 350 gtc acc atg act aca gtt ggc tat gga gac atg gca ccc gtc act gtg 1463 Val Thr Met Thr Thr Val Gly Tyr Gly Asp Met Ala Pro Val Thr Val 355 360 365 ggt ggc aag ata gtg ggc tct ctg tgt gcc att gcg ggc gtg ctg act 1511 Gly Gly Lys Ile Val Gly Ser Leu Cys Ala Ile Ala Gly Val Leu Thr 370 375 380 385 att tcc ctg cca gtg ccc gtc att gtc tcc aat ttc agc tac ttt tat 1559 Ile Ser Leu Pro Val Pro Val Ile Val Ser Asn Phe Ser Tyr Phe Tyr 390 395 400 cac cgg gag aca gag ggc gaa gag gct ggg atg ttc agc cat gtg gac 1607 His Arg Glu Thr Glu Gly Glu Glu Ala Gly Met Phe Ser His Val Asp 405 410 415 acg cag cct tgt ggc cca ctg gag ggc aag gcc aat ggg ggg ctg gtg 1655 Thr Gln Pro Cys Gly Pro Leu Glu Gly Lys Ala Asn Gly Gly Leu Val 420 425 430 gac ggg gag gta cct gag cta cca cct cca ctc tgg gca ccc cca ggg 1703 Asp Gly Glu Val Pro Glu Leu Pro Pro Pro Leu Trp Ala Pro Pro Gly 435 440 445 aaa cac ctg gtc acc gaa gtg tga ggaacagttg aggtctgcag gacctcacac 1757 Lys His Leu Val Thr Glu Val 450 455 ctccctagag ggagggaggg agggcagggt ggagggcaag gctgggggga ggggattggg 1817 tttaggaaga gctaggttaa gtcataacga gtggggaaac actgagtctt gttgggtctt 1877 gggttgtgtg gtttggtagc tcctgtgggt acctcctgaa gcagcagcga atggcaatgg 1937 gttgtgttgt gttaatgaag actcaattgg ttcatattac tctgagttgt gcaaagctca 1997 tggagccttt tggggtagtg ttgagatagg tttggtcgta tcattttgtg agtttcctag 2057 gtcagtgttg ggtttggttg ggttgtgagt ctgggatagt gtggtccagc tgcattgtgt 2117 aggattctgt ggtttggtgg gtcccctagg gccatgttgg gtcaagttag atggtccccc 2177 atggcattgt tgagatcgaa tgtgtgtggt gttaagtttc gttgagacat ggtggaaatt 2237 gtgtagctct gtgattcttc caggggcatg ttattttagg ttctgtgaac ttgcgagtca 2297 tgtagaaatg tgaagagtcc agtggtagaa tttgagcttt ctaggtcaca ttgggttaag 2357 tttgtatgac caaatgaatc ttgtagggtt ctgttgggct taactgtgta gaggtgtgtg 2417 gctggacatt tttcgtggcc acagcgagtt gagttgtgtt gaattgtaca accatatgag 2477 ccttgtaagg ccagttcagt tgggtcatgc cactgtttga gtctcatagg gccatgctga 2537 attgagttcc attgagttgt gtcactatgt gagtcctaca ggaagttggg ttgagttgga 2597 ctgtgcgaac gagttccata gggccacatc gggctgtttt gcatttagtg gtagcaccag 2657 gacccaaagg aaatagcagt ggggaagcat catgtatctg ggagcatgca gtggcgaggg 2717 ctctgggagg tgtgccgagc tggctcccca gctcgctgta gggggcggga ctggattctg 2777 tatccatggg attgggtgtt catccagagg cgactgggta aattaggaag aggtggatgc 2837 tcctcctgtt taccccacat ccacttcatt gtgctgttca ctcccattct cccctacagt 2897 tttatgctca gacatggagg tcagagccac aagggaaagg ggagaggggg agaaaactgt 2957 actctgtcca gacatgatag agggacagag ccaaaaggat agagaaagag acccagaaaa 3017 aggaagaggt ggaaacccag agagacagag acccaaaggg agagaaacag agactcaggg 3077 agagggagac aatgacctgg agggtggggt atggcagaga cgcagaagag aggaacagaa 3137 atccagagtg gggagacaga gaccaagagc aggggataga agccgggcga agtggcccat 3197 gcctgtaatc tcagcactct gggagaccga ggaaggggga ttgattgagg ccaggagttc 3257 aagaccagcc tgggcaacat ggtgagaccc catctctaca aaaaatacaa aaattagctg 3317 agtgtggtgg cacatgcctg tgatcccagc tactcaggaa gctgaggcag aaagatccct 3377 tgaccctgag aggtagaggc tgcattgagc catgattgca ccactgcact ccagcctggg 3437 caacagaggg agcccccgtc tcaacaaaca aacaaaaaga gccagtgggg gagggaggga 3497 cagagaccca gagggcagcg tcagacaccc agagttggag acagaacaac agagtctcag 3557 ggaaagagaa ccacaataga aaaaggcaga aaaggccggg cgcggtggct catgcctgta 3617 accccagcac tttgggaggc cgaggtgggc aaattacgag gtcaggagat ccagaccatc 3677 ctggctaaca cggtgaaacc ccgtctctac taaaaataca aaaaaattag ccgggtgcgg 3737 tggcgggcac ctgtagtccc agctactcgg gaggctgagg caggagaatg gcatgaacct 3797 gggaggcgga gcttgcagtg agccgagatt gcgccactgc actccagcct gggcagcaga 3857 gcaacactct gtctcaaaaa aaaaaagaaa agaaaagaaa aagccagaaa aagttggtgc 3917 ccctgaaccc aagagtgatg tacagtctat tccatagaat cacagaacaa tcctgaacca 3977 ggcctgtcac ctaccctccc tgcagctcag gaaggctgtc agacaggctg ggggcctcac 4037 tctgttttcc aggggagaaa cctgagtctc agagcagggg agtggcttcc caaggtctca 4097 cagcttgtcc ccaggggcca ggcaggctgt ctgtctgctt cacatgtccc catcagcctg 4157 ctgggacaca cgggtcctcc tgagtcccgt agcctcattt cttacagacg gggaaactga 4217 ggctcagagc agcaggtgtt acccaaggtc acaaggccga acattttcag aaatctttca 4277 gaactcaaag ggcatttaga ggaagaaggc tgaaatcact aacacatata gggcttcctt 4337 tggtatcaaa gtactttact tgggttaatt tatta 4372 <210> SEQ ID NO 2 <211> LENGTH: 456 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Met Glu Pro Arg Cys Pro Pro Pro Cys Gly Cys Cys Glu Arg Leu Val 1 5 10 15 Leu Asn Val Ala Gly Leu Arg Phe Glu Thr Arg Ala Arg Thr Leu Gly 20 25 30 Arg Phe Pro Asp Thr Leu Leu Gly Asp Pro Ala Arg Arg Gly Arg Phe 35 40 45 Tyr Asp Asp Ala Arg Arg Glu Tyr Phe Phe Asp Arg His Arg Pro Ser 50 55 60 Phe Asp Ala Val Leu Tyr Tyr Tyr Gln Ser Gly Gly Arg Leu Arg Arg 65 70 75 80 Pro Ala His Val Pro Leu Asp Val Phe Leu Glu Glu Val Ala Phe Tyr 85 90 95 Gly Leu Gly Ala Ala Ala Leu Ala Arg Leu Arg Glu Asp Glu Gly Cys 100 105 110 Pro Val Pro Pro Glu Arg Pro Leu Pro Arg Arg Ala Phe Ala Arg Gln 115 120 125 Leu Trp Leu Leu Phe Glu Phe Pro Glu Ser Ser Gln Ala Ala Arg Val 130 135 140 Leu Ala Val Val Ser Val Leu Val Ile Leu Val Ser Ile Val Val Phe 145 150 155 160 Cys Leu Glu Thr Leu Pro Asp Phe Arg Asp Asp Arg Asp Gly Thr Gly 165 170 175 Leu Ala Ala Ala Ala Ala Ala Gly Pro Phe Pro Ala Pro Leu Asn Gly 180 185 190 Ser Ser Gln Met Pro Gly Asn Pro Pro Arg Leu Pro Phe Asn Asp Pro 195 200 205 Phe Phe Val Val Glu Thr Leu Cys Ile Cys Trp Phe Ser Phe Glu Leu 210 215 220 Leu Val Arg Leu Leu Val Cys Pro Ser Lys Ala Ile Phe Phe Lys Asn 225 230 235 240 Val Met Asn Leu Ile Asp Phe Val Ala Ile Leu Pro Tyr Phe Val Ala 245 250 255 Leu Gly Thr Glu Leu Ala Arg Gln Arg Gly Val Gly Gln Gln Ala Met 260 265 270 Ser Leu Ala Ile Leu Arg Val Ile Arg Leu Val Arg Val Phe Arg Ile 275 280 285 Phe Lys Leu Ser Arg His Ser Lys Gly Leu Gln Ile Leu Gly Gln Thr 290 295 300 Leu Arg Ala Ser Met Arg Glu Leu Gly Leu Leu Ile Phe Phe Leu Phe 305 310 315 320 Ile Gly Val Val Leu Phe Ser Ser Ala Val Tyr Phe Ala Glu Val Asp 325 330 335 Arg Val Asp Ser His Phe Thr Ser Ile Pro Glu Ser Phe Trp Trp Ala 340 345 350 Val Val Thr Met Thr Thr Val Gly Tyr Gly Asp Met Ala Pro Val Thr 355 360 365 Val Gly Gly Lys Ile Val Gly Ser Leu Cys Ala Ile Ala Gly Val Leu 370 375 380 Thr Ile Ser Leu Pro Val Pro Val Ile Val Ser Asn Phe Ser Tyr Phe 385 390 395 400 Tyr His Arg Glu Thr Glu Gly Glu Glu Ala Gly Met Phe Ser His Val 405 410 415 Asp Thr Gln Pro Cys Gly Pro Leu Glu Gly Lys Ala Asn Gly Gly Leu 420 425 430 Val Asp Gly Glu Val Pro Glu Leu Pro Pro Pro Leu Trp Ala Pro Pro 435 440 445 Gly Lys His Leu Val Thr Glu Val 450 455 <210> SEQ ID NO 3 <211> LENGTH: 706 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <223> OTHER INFORMATION: N=A,T,G or C <300> PUBLICATION INFORMATION: <301> AUTHORS: Zabarovsky et al. <302> TITLE: NotI clones in the analysis of the human genome <303> JOURNAL: Nucleic Acids Research <304> VOLUME: 28 <305> ISSUE: 7 <306> PAGES: 1635- 1639 <307> DATE: 2000-__-__ <308> DATABASE ACCESSION NUMBER: GenBank/AQ939522 <309> DATABASE ENTRY DATE: 2000-04-03 <400> SEQUENCE: 3 gcggccgcgt tgaacgagcc aggcctggct tccaaggtcc cggcacgcga gtgcaaggca 60 ggatcctggg aggaagtctg ggataaccag gtcacggagg gccttggcgc agcggctact 120 gaccaatgtg taaagaggag ctgggtattt aaatgatgat taaggctgtc cccgtgtcct 180 agccccagcc tgaccctccc tgaacacttt cctccctgca gttccccgct cggctgaatg 240 gctccagcca aatgcctgga aatccacccc gcctgccctt caatgacccg ttcttcgtgg 300 tggagacgct gtgtatttgt tggttctcct ttgagctgct ggtacgcctt ctggtctgtc 360 caagcaaggc tatcttcttc aagaacgtga tgaacctcat cgattttgtg gctatccttc 420 cctactttgt ggcactgggc acccgagctg gcccggcagc gaggggtggg ccancaggcc 480 atgtcacttg gccattcttg agaagtatcc gattggtgcg tgtnttccgg aatcttcaag 540 ctgtccccgn actnaaaang ggccttnnaa ttntttgggc caaanccntt ngggcttcat 600 tgcgttgaag ctggggcctc cctaatcttt tttcctcttt cattcggtgg tgggcctctt 660 ttttagccgc cctctacttt tgccgaagtt gacccgggtg ggacct 706 <210> SEQ ID NO 4 <211> LENGTH: 1599 <212> TYPE: DNA <213> ORGANISM: Mus musculus <300> PUBLICATION INFORMATION: <301> AUTHORS: Kalman et al. <302> TITLE: Genomic Organization, Chromosomal Localization, Tissue Distribution, and Biophysical Characterization of a Novel Mammalian Shaker-related Voltage-gated Potassium Channel, Kv1.7 <303> JOURNAL: Journal of Biological Chemistry <304> VOLUME: 273 <305> ISSUE: 10 <306> PAGES: 58515857 <307> DATE: 1998-03-06 <308> DATABASE ACCESSION NUMBER: GenBank/AF032099 <309> DATABASE ENTRY DATE: 1998-04-04 <400> SEQUENCE: 4 atgactacaa ggaaagctca agagatccac ggaaaagcgc cgggtggcag tgtttccaca 60 ggtgtgggaa cggcagaggg cgcccctagc cccgcggggg taacaccgcc ccctcccccg 120 cgccctggcc ggactttcca tgctattttt acccgccgac accggacacc cgactggggt 180 ggctgcggcg tcggggccac acgtccgttc accggtcgcc cgggctgtgc gcgccatgga 240 gccacggtgc ccgccgccct gcgctgctgc gagcggctgg tgctcaacgt ggccgggttg 300 cgcttcgaga cccgcgcgcg cacgctcggc cgcttcccgg acacgctgct gggggacccg 360 gtgcgccgca gccgcttcta cgacggcgcg cgcgccgagt atttcttcga ccgacaccgg 420 cccagcttcg atgcggtgct ctactactac cagtcgggcg gccggctgag acggccggcg 480 cacgtgcccc tcgacgtctt cctggaggag gtgtccttct acgggctggg gcggcggctg 540 gcgcggctgc gggaggacga gggctgcgcg gtcgccgagc ggccgctgcc cccgcccttt 600 gcgcgtcagc tctggctgct cttcgaattt cctgagagct cgcaggctgc gcgcgtgctc 660 gccgtggtct ccgtactcgt catcctggtc tccatcgtgg tcttttgcct cgagacactg 720 ccagacttcc gcgacgaccg cgatgacccg gggctcgcgc cggtagcggc tgctactggc 780 tcgttcctcg cccgactgaa tggctccagt cccatgccag gagcccctcc ccgacagccc 840 ttcaacgatc cattctttgt ggtggagacc ctgtgtatct gctggttctc ctttgagctg 900 ctggtgcatc tggtggcctg ccctagcaaa gctgtgttct tcaagaatgt gatgaaccta 960 attgacttcg tggccatcct gccttacttc gtggccctgg gcacggagtt agcccggcag 1020 cggggtgtgg gccagccggc tatgtccctg gccatcctaa gggtcatccg attggtgcgt 1080 gtcttccgca tcttcaagct ctccaggcat tcgaagggtc tacagatctt gggtcagaca 1140 ctgcgggctt ccatgcgtga gctaggtctc ctcatcttct tcctcttcat tggcgtggtc 1200 ctcttttcca gcgcagtcta ctttgctgaa gtggaccggg tggacaccca tttcaccagc 1260 atcccggagt ccttttggtg ggcagtggtc accatgacca cggttggcta tggggacatg 1320 gcacccgtca ccgtgggtgg caagatcgtg ggctctctgt gtgccattgc aggtgtgctc 1380 accatctctc tgcctgtgcc tgtcattgtc tctaacttta gctactttta ccaccgggag 1440 acagagggcg aagaggcagg gatgtacagc catgtggaca cacagccctg cggtaccctg 1500 gagggcaagg ctaatggggg gctggtggac tctgaggtgc ctgaactcct cccaccactc 1560 tggccccctg cagggaaaca catggtgact gaggtgtga 1599 <210> SEQ ID NO 5 <211> LENGTH: 3473 <212> TYPE: DNA <213> ORGANISM: Mus musculus <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (262)..(1860) <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/NM_010596 <309> DATABASE ENTRY DATE: 2000-01-25 <400> SEQUENCE: 5 ctgcagatag tctcgggtgg ctcatgactg tcacccgggc aatccgaaga tgaggcagag 60 gattgccaca agttcgcggt cagcttaaat gacaggctga ggagactgtc taaataacaa 120 acaaacaaat aaatagccat gatgccatac gcctgcaatc ccagcatttg ggaggtggag 180 gcaggaggat cataaattca aggtcagttc agctacataa gacctcgggt catgaatcca 240 aaagccaaac aaataaaata g atg act aca agg aaa gct caa gag atc cac 291 Met Thr Thr Arg Lys Ala Gln Glu Ile His 1 5 10 gga aaa gcg ccg ggt ggc agt gtt tcc aca ggt gtg gga acg gca gag 339 Gly Lys Ala Pro Gly Gly Ser Val Ser Thr Gly Val Gly Thr Ala Glu 15 20 25 ggc gcc cct agc ccc gcg ggg gta aca ccg ccc cct ccc ccg cgc cct 387 Gly Ala Pro Ser Pro Ala Gly Val Thr Pro Pro Pro Pro Pro Arg Pro 30 35 40 ggc cgg act ttc cat gct att ttt acc cgc cga cac cgg aca ccc gac 435 Gly Arg Thr Phe His Ala Ile Phe Thr Arg Arg His Arg Thr Pro Asp 45 50 55 tgg ggt ggc tgc ggc gtc ggg gcc aca cgt ccg ttc acc ggt cgc ccg 483 Trp Gly Gly Cys Gly Val Gly Ala Thr Arg Pro Phe Thr Gly Arg Pro 60 65 70 ggc tgt gcg cgc cat gga gcc acg gtg ccc gcc gcc ctg cgc tgc tgc 531 Gly Cys Ala Arg His Gly Ala Thr Val Pro Ala Ala Leu Arg Cys Cys 75 80 85 90 gag cgg ctg gtg ctc aac gtg gcc ggg ttg cgc ttc gag acc cgc gcg 579 Glu Arg Leu Val Leu Asn Val Ala Gly Leu Arg Phe Glu Thr Arg Ala 95 100 105 cgc acg ctc ggc cgc ttc ccg gac acg ctg ctg ggg gac ccg gtg cgc 627 Arg Thr Leu Gly Arg Phe Pro Asp Thr Leu Leu Gly Asp Pro Val Arg 110 115 120 cgc agc cgc ttc tac gac ggc gcg cgc gcc gag tat ttc ttc gac cga 675 Arg Ser Arg Phe Tyr Asp Gly Ala Arg Ala Glu Tyr Phe Phe Asp Arg 125 130 135 cac cgg ccc agc ttc gat gcg gtg ctc tac tac tac cag tcg ggc ggc 723 His Arg Pro Ser Phe Asp Ala Val Leu Tyr Tyr Tyr Gln Ser Gly Gly 140 145 150 cgg ctg aga cgg ccg gcg cac gtg ccc ctc gac gtc ttc ctg gag gag 771 Arg Leu Arg Arg Pro Ala His Val Pro Leu Asp Val Phe Leu Glu Glu 155 160 165 170 gtg tcc ttc tac ggg ctg ggg cgg cgg ctg gcg cgg ctg cgg gag gac 819 Val Ser Phe Tyr Gly Leu Gly Arg Arg Leu Ala Arg Leu Arg Glu Asp 175 180 185 gag ggc tgc gcg gtc gcc gag cgg ccg ctg ccc ccg ccc ttt gcg cgt 867 Glu Gly Cys Ala Val Ala Glu Arg Pro Leu Pro Pro Pro Phe Ala Arg 190 195 200 cag ctc tgg ctg ctc ttc gaa ttt cct gag agc tcg cag gct gcg cgc 915 Gln Leu Trp Leu Leu Phe Glu Phe Pro Glu Ser Ser Gln Ala Ala Arg 205 210 215 gtg ctc gcc gtg gtc tcc gta ctc gtc atc ctg gtc tcc atc gtg gtc 963 Val Leu Ala Val Val Ser Val Leu Val Ile Leu Val Ser Ile Val Val 220 225 230 ttt tgc ctc gag aca ctg cca gac ttc cgc gac gac cgc gat gac ccg 1011 Phe Cys Leu Glu Thr Leu Pro Asp Phe Arg Asp Asp Arg Asp Asp Pro 235 240 245 250 ggg ctc gcg ccg gta gcg gct gct act ggc tcg ttc ctc gct cgg ctc 1059 Gly Leu Ala Pro Val Ala Ala Ala Thr Gly Ser Phe Leu Ala Arg Leu 255 260 265 aat ggc tcc agt ccc atg cca gga gcc cct ccc cga cag ccc ttc aac 1107 Asn Gly Ser Ser Pro Met Pro Gly Ala Pro Pro Arg Gln Pro Phe Asn 270 275 280 gat cca ttc ttt gtg gtg gag acc ctg tgt atc tgc tgg ttc tcc ttt 1155 Asp Pro Phe Phe Val Val Glu Thr Leu Cys Ile Cys Trp Phe Ser Phe 285 290 295 gag ctg ctg gtg cat ctg gtg gcc tgc cct agc aaa gct gtg ttc ttc 1203 Glu Leu Leu Val His Leu Val Ala Cys Pro Ser Lys Ala Val Phe Phe 300 305 310 aag aat gtg atg aac cta att gac ttc gtg gcc atc ctg cct tac ttc 1251 Lys Asn Val Met Asn Leu Ile Asp Phe Val Ala Ile Leu Pro Tyr Phe 315 320 325 330 gtg gcc ctg ggc acg gag tta gcc cgg cag cgg ggt gtg ggc cag ccg 1299 Val Ala Leu Gly Thr Glu Leu Ala Arg Gln Arg Gly Val Gly Gln Pro 335 340 345 gct atg tcc ctg gcc atc cta agg gtc atc cga ttg gtg cgt gtc ttc 1347 Ala Met Ser Leu Ala Ile Leu Arg Val Ile Arg Leu Val Arg Val Phe 350 355 360 cgc atc ttc aag ctc tcc agg cat tcg aag ggt cta cag atc ttg ggt 1395 Arg Ile Phe Lys Leu Ser Arg His Ser Lys Gly Leu Gln Ile Leu Gly 365 370 375 cag aca ctg cgg gct tcc atg cgt gag cta ggt ctc ctc atc ttc ttc 1443 Gln Thr Leu Arg Ala Ser Met Arg Glu Leu Gly Leu Leu Ile Phe Phe 380 385 390 ctc ttc att ggc gtg gtc ctc ttt tcc agc gca gtc tac ttt gct gaa 1491 Leu Phe Ile Gly Val Val Leu Phe Ser Ser Ala Val Tyr Phe Ala Glu 395 400 405 410 gtg gac cgg gtg gac acc cat ttc acc agc atc ccg gag tcc ttt tgg 1539 Val Asp Arg Val Asp Thr His Phe Thr Ser Ile Pro Glu Ser Phe Trp 415 420 425 tgg gca gtg gtc acc atg acc acg gtt ggc tat ggg gac atg gca ccc 1587 Trp Ala Val Val Thr Met Thr Thr Val Gly Tyr Gly Asp Met Ala Pro 430 435 440 gtc acc gtg ggt ggc aag atc gtg ggc tct ctg tgt gcc att gca ggt 1635 Val Thr Val Gly Gly Lys Ile Val Gly Ser Leu Cys Ala Ile Ala Gly 445 450 455 gtg ctc acc atc tct ctg cct gtg cct gtc att gtc tct aac ttt agc 1683 Val Leu Thr Ile Ser Leu Pro Val Pro Val Ile Val Ser Asn Phe Ser 460 465 470 tac ttt tac cac cgg gag aca gag ggc gaa gag gca ggg atg tac agc 1731 Tyr Phe Tyr His Arg Glu Thr Glu Gly Glu Glu Ala Gly Met Tyr Ser 475 480 485 490 cat gtg gac aca cag ccc tgc ggt acc ctg gag ggc aag gct aat ggg 1779 His Val Asp Thr Gln Pro Cys Gly Thr Leu Glu Gly Lys Ala Asn Gly 495 500 505 ggg ctg gtg gac tct gag gtg cct gaa ctc ctc cca cca ctc tgg ccc 1827 Gly Leu Val Asp Ser Glu Val Pro Glu Leu Leu Pro Pro Leu Trp Pro 510 515 520 cct gca ggg aaa cac atg gtg act gag gtg tga gggtcaactg gggtctccag 1880 Pro Ala Gly Lys His Met Val Thr Glu Val 525 530 ggagcagtgg ggtgggaggg aggagggaag gcaggtcagg tgctgggtta aggactaaga 1940 tggtaacaaa atcttaatct gaaggcatgt cacatggtgg cgggtacaga ttcctagggg 2000 gaccttatgt gacaggaatt gccaggattt gggttgtgtc cagggctccc cccattgatt 2060 gcgcaatgtg gtagagctgt gcaaatgtcc aggggctcta tgggtagcac tgtaagagac 2120 ttggccatag attgtgagtt tcctaggtgt tcgtggggtc ccactggggg caagtgtggt 2180 cccgttaaca cttgataggt actaatagaa ctttgggtcc tctagggcca agtcggctcc 2240 tgtaggtctc tggagcactg ttaaagagtg tgagcttgtg gctacatggt cacacacaga 2300 ggttatgtgg tgatacatag cagattgtgt ggattcatgt ttcttctagg actcaagtta 2360 ttttagattc tgtgagctct ggagtcatgc agacaggatg tgatcactct gggtcctgat 2420 ggaaaaaggg ttagggtata aaagatagac agaggcagag actcagataa agggacagag 2480 acacccccac acacacacac aacacacaat tctctgtgtt gtgcagggtt ataggactgg 2540 aatcatttta gggccatgca aagctgagat ggtgaccccc atgtgtctcc gaacagttga 2600 gtctgatgac ttctacggtc tcatgggact tgtgttactg tgagtcctgt ggaacttttg 2660 gttgaatttg actgtatgtg agggccattt taaacagtag atcagggtca cagcacagat 2720 aaaactaact acaagggagc aagcatgggc acgtggatgt gtgtggcccg ttgaacaagt 2780 ttactcaggg ttatgcattg tagagctggt agtgtctgta tctctgggtc cccctgcccg 2840 aagcacctag aaagacgatg ggaactagta acctgcctgt cttgctcatg tgggacccat 2900 atttctatgt tgtcccatgc tgtagtacaa agattcagag gctggttgga gccacaagga 2960 aagaaaacac agtagggcaa gagtaggtac ttgggaaaag atgtggcagg ggacagagat 3020 ctagaagaaa gaaagatgga gagaaggagc aggaggagca ggggaggggg aaagagggaa 3080 gggaaggagg gagagacaga gcaggtaaag aggaagagat gtgggggggg gggggagaag 3140 gacctggagc ccaagggtca tcctctctat tctctgagtc ataacagact ctaagctatg 3200 gcgtcagcat cccttagagc caaggaaggt caccacactc ctggaggtgc tctgtgtttc 3260 ctaggacaga aacccaaggc tgtagtgtgc tgtgcttcct caagttaccc agcggtcata 3320 gaccaagctg gtgccaggtg gcctgcctgt gacaccccca caacttctgg tgtgcaggta 3380 ttgcctgagg ccactggtcc tgtgtccttt gtttatccct taaaacaggg tccctctttg 3440 tagtgttggc tgtcctggaa ctcactacgt aga 3473 <210> SEQ ID NO 6 <211> LENGTH: 532 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 6 Met Thr Thr Arg Lys Ala Gln Glu Ile His Gly Lys Ala Pro Gly Gly 1 5 10 15 Ser Val Ser Thr Gly Val Gly Thr Ala Glu Gly Ala Pro Ser Pro Ala 20 25 30 Gly Val Thr Pro Pro Pro Pro Pro Arg Pro Gly Arg Thr Phe His Ala 35 40 45 Ile Phe Thr Arg Arg His Arg Thr Pro Asp Trp Gly Gly Cys Gly Val 50 55 60 Gly Ala Thr Arg Pro Phe Thr Gly Arg Pro Gly Cys Ala Arg His Gly 65 70 75 80 Ala Thr Val Pro Ala Ala Leu Arg Cys Cys Glu Arg Leu Val Leu Asn 85 90 95 Val Ala Gly Leu Arg Phe Glu Thr Arg Ala Arg Thr Leu Gly Arg Phe 100 105 110 Pro Asp Thr Leu Leu Gly Asp Pro Val Arg Arg Ser Arg Phe Tyr Asp 115 120 125 Gly Ala Arg Ala Glu Tyr Phe Phe Asp Arg His Arg Pro Ser Phe Asp 130 135 140 Ala Val Leu Tyr Tyr Tyr Gln Ser Gly Gly Arg Leu Arg Arg Pro Ala 145 150 155 160 His Val Pro Leu Asp Val Phe Leu Glu Glu Val Ser Phe Tyr Gly Leu 165 170 175 Gly Arg Arg Leu Ala Arg Leu Arg Glu Asp Glu Gly Cys Ala Val Ala 180 185 190 Glu Arg Pro Leu Pro Pro Pro Phe Ala Arg Gln Leu Trp Leu Leu Phe 195 200 205 Glu Phe Pro Glu Ser Ser Gln Ala Ala Arg Val Leu Ala Val Val Ser 210 215 220 Val Leu Val Ile Leu Val Ser Ile Val Val Phe Cys Leu Glu Thr Leu 225 230 235 240 Pro Asp Phe Arg Asp Asp Arg Asp Asp Pro Gly Leu Ala Pro Val Ala 245 250 255 Ala Ala Thr Gly Ser Phe Leu Ala Arg Leu Asn Gly Ser Ser Pro Met 260 265 270 Pro Gly Ala Pro Pro Arg Gln Pro Phe Asn Asp Pro Phe Phe Val Val 275 280 285 Glu Thr Leu Cys Ile Cys Trp Phe Ser Phe Glu Leu Leu Val His Leu 290 295 300 Val Ala Cys Pro Ser Lys Ala Val Phe Phe Lys Asn Val Met Asn Leu 305 310 315 320 Ile Asp Phe Val Ala Ile Leu Pro Tyr Phe Val Ala Leu Gly Thr Glu 325 330 335 Leu Ala Arg Gln Arg Gly Val Gly Gln Pro Ala Met Ser Leu Ala Ile 340 345 350 Leu Arg Val Ile Arg Leu Val Arg Val Phe Arg Ile Phe Lys Leu Ser 355 360 365 Arg His Ser Lys Gly Leu Gln Ile Leu Gly Gln Thr Leu Arg Ala Ser 370 375 380 Met Arg Glu Leu Gly Leu Leu Ile Phe Phe Leu Phe Ile Gly Val Val 385 390 395 400 Leu Phe Ser Ser Ala Val Tyr Phe Ala Glu Val Asp Arg Val Asp Thr 405 410 415 His Phe Thr Ser Ile Pro Glu Ser Phe Trp Trp Ala Val Val Thr Met 420 425 430 Thr Thr Val Gly Tyr Gly Asp Met Ala Pro Val Thr Val Gly Gly Lys 435 440 445 Ile Val Gly Ser Leu Cys Ala Ile Ala Gly Val Leu Thr Ile Ser Leu 450 455 460 Pro Val Pro Val Ile Val Ser Asn Phe Ser Tyr Phe Tyr His Arg Glu 465 470 475 480 Thr Glu Gly Glu Glu Ala Gly Met Tyr Ser His Val Asp Thr Gln Pro 485 490 495 Cys Gly Thr Leu Glu Gly Lys Ala Asn Gly Gly Leu Val Asp Ser Glu 500 505 510 Val Pro Glu Leu Leu Pro Pro Leu Trp Pro Pro Ala Gly Lys His Met 515 520 525 Val Thr Glu Val 530 <210> SEQ ID NO 7 <211> LENGTH: 522 <212> TYPE: DNA <213> ORGANISM: Mus musculus <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/AI322534 <309> DATABASE ENTRY DATE: 1998-12-23 <400> SEQUENCE: 7 gtttccacag gtgtgggaac ggcagagggc gcccctagcc ccgcgggggt aacaccgccc 60 cctcccccgc gccctggccg gactttccat gctattttta cccgccgaca ccggacaccc 120 gactggggtg gctgcggcgt cggggccaca cgtccgttca ccggtcgccc gggctgtgcg 180 cgccatggag ccacggtgcc cgccgccctg cggctgctgc gagcggctgg tgctcaacgt 240 ggccgggttg cgcttcgaga cccgcgcgcg cacgctcggc cgcttcccgg acacgctgct 300 gggggacccg gtgcgccgca gccgcttcta cgacggcgcg cgccgcgagt atttcttcga 360 ccgacaccgg cccagcttcg atgcggtgct ctactactac cagtcgggcg ggcggctgag 420 accggcggcg caccttggcc ctcgacggtc ttcctggagg aggtgtcctt ctacgggctg 480 ggcgcggcgg cgcttgcgcg gctgcgggag gacgagggct gc 522 <210> SEQ ID NO 8 <211> LENGTH: 468 <212> TYPE: DNA <213> ORGANISM: Mus musculus <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/AI324179 <309> DATABASE ENTRY DATE: 1998-12-23 <400> SEQUENCE: 8 tcctcccgca gccgcgccag cgccgccgcg cccagcccgt agaaggacac ctcctccagg 60 aagacgtcga ggggcaggtg cgccggccgt ctcagccggc cgcccgactg gtagtagtag 120 agcaccgcat cgaagctggg ccggtgtcgg tcgaagaaat actcgcggcg cgcgccgtcg 180 tagaagcggc tgcggcgcac cgggtccccc agcagcgtgt ccgggaagcg gccgagcgtg 240 cgcgcgcggg tctcgaagcg caacccggcc acgttgagca ccagccgctc gcagcagccg 300 cagggcggcg ggcaccgtgg ctccatggcg cgcacagccc gggcgaccgg tgaacggacg 360 tgtggccccg acgccgcagc caccccagtc gggtgtccgg tgtcggcggg taaaaatagc 420 atggaaagtc cggccagggc gcggtggagg gggcggtgtt acccccgc 468 <210> SEQ ID NO 9 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR primer <400> SEQUENCE: 9 aaagctcaag agatccacgg aaaagcg 27 <210> SEQ ID NO 10 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR primer <400> SEQUENCE: 10 cgactggtag tagtagagca ccgcatc 27 <210> SEQ ID NO 11 <211> LENGTH: 3474 <212> TYPE: DNA <213> ORGANISM: Mus musculus <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (497)..(1861) <400> SEQUENCE: 11 ctgcagatag tctcgggtgg ctcatgactg tcacccgggc aatccgaaga tgaggcagag 60 gattgccaca agttcgcggt cagcttaaat gacaggctga ggagactgtc taaataacaa 120 acaaacaaat aaatagccat gatgccatac gcctgcaatc ccagcatttg ggaggtggag 180 gcaggaggat cataaattca aggtcagttc agctacataa gacctcgggt catgaatcca 240 aaagccaaac aaataaaata gatgactaca aggaaagctc aagagatcca cggaaaagcg 300 ccgggtggca gtgtttccac aggtgtggga acggcagagg gcgcccctag ccccgcgggg 360 gtaacaccgc cccctccccc gcgccctggc cggactttcc atgctatttt tacccgccga 420 caccggacac ccgactgggg tggctgcggc gtcggggcca cacgtccgtt caccggtcgc 480 ccgggctgtg cgcgcc atg gag cca cgg tgc ccg ccg ccc tgc ggc tgc tgc 532 Met Glu Pro Arg Cys Pro Pro Pro Cys Gly Cys Cys 1 5 10 gag cgg ctg gtg ctc aac gtg gcc ggg ttg cgc ttc gag acc cgc gcg 580 Glu Arg Leu Val Leu Asn Val Ala Gly Leu Arg Phe Glu Thr Arg Ala 15 20 25 cgc acg ctc ggc cgc ttc ccg gac acg ctg ctg ggg gac ccg gtg cgc 628 Arg Thr Leu Gly Arg Phe Pro Asp Thr Leu Leu Gly Asp Pro Val Arg 30 35 40 cgc agc cgc ttc tac gac ggc gcg cgc gcc gag tat ttc ttc gac cga 676 Arg Ser Arg Phe Tyr Asp Gly Ala Arg Ala Glu Tyr Phe Phe Asp Arg 45 50 55 60 cac cgg ccc agc ttc gat gcg gtg ctc tac tac tac cag tcg ggc ggc 724 His Arg Pro Ser Phe Asp Ala Val Leu Tyr Tyr Tyr Gln Ser Gly Gly 65 70 75 cgg ctg aga cgg ccg gcg cac gtg ccc ctc gac gtc ttc ctg gag gag 772 Arg Leu Arg Arg Pro Ala His Val Pro Leu Asp Val Phe Leu Glu Glu 80 85 90 gtg tcc ttc tac ggg ctg ggg cgg cgg ctg gcg cgg ctg cgg gag gac 820 Val Ser Phe Tyr Gly Leu Gly Arg Arg Leu Ala Arg Leu Arg Glu Asp 95 100 105 gag ggc tgc gcg gtc gcc gag cgg ccg ctg ccc ccg ccc ttt gcg cgt 868 Glu Gly Cys Ala Val Ala Glu Arg Pro Leu Pro Pro Pro Phe Ala Arg 110 115 120 cag ctc tgg ctg ctc ttc gaa ttt cct gag agc tcg cag gct gcg cgc 916 Gln Leu Trp Leu Leu Phe Glu Phe Pro Glu Ser Ser Gln Ala Ala Arg 125 130 135 140 gtg ctc gcc gtg gtc tcc gta ctc gtc atc ctg gtc tcc atc gtg gtc 964 Val Leu Ala Val Val Ser Val Leu Val Ile Leu Val Ser Ile Val Val 145 150 155 ttt tgc ctc gag aca ctg cca gac ttc cgc gac gac cgc gat gac ccg 1012 Phe Cys Leu Glu Thr Leu Pro Asp Phe Arg Asp Asp Arg Asp Asp Pro 160 165 170 ggg ctc gcg ccg gta gcg gct gct act ggc tcg ttc ctc gct cgg ctc 1060 Gly Leu Ala Pro Val Ala Ala Ala Thr Gly Ser Phe Leu Ala Arg Leu 175 180 185 aat ggc tcc agt ccc atg cca gga gcc cct ccc cga cag ccc ttc aac 1108 Asn Gly Ser Ser Pro Met Pro Gly Ala Pro Pro Arg Gln Pro Phe Asn 190 195 200 gat cca ttc ttt gtg gtg gag acc ctg tgt atc tgc tgg ttc tcc ttt 1156 Asp Pro Phe Phe Val Val Glu Thr Leu Cys Ile Cys Trp Phe Ser Phe 205 210 215 220 gag ctg ctg gtg cat ctg gtg gcc tgc cct agc aaa gct gtg ttc ttc 1204 Glu Leu Leu Val His Leu Val Ala Cys Pro Ser Lys Ala Val Phe Phe 225 230 235 aag aat gtg atg aac cta att gac ttc gtg gcc atc ctg cct tac ttc 1252 Lys Asn Val Met Asn Leu Ile Asp Phe Val Ala Ile Leu Pro Tyr Phe 240 245 250 gtg gcc ctg ggc acg gag tta gcc cgg cag cgg ggt gtg ggc cag ccg 1300 Val Ala Leu Gly Thr Glu Leu Ala Arg Gln Arg Gly Val Gly Gln Pro 255 260 265 gct atg tcc ctg gcc atc cta agg gtc atc cga ttg gtg cgt gtc ttc 1348 Ala Met Ser Leu Ala Ile Leu Arg Val Ile Arg Leu Val Arg Val Phe 270 275 280 cgc atc ttc aag ctc tcc agg cat tcg aag ggt cta cag atc ttg ggt 1396 Arg Ile Phe Lys Leu Ser Arg His Ser Lys Gly Leu Gln Ile Leu Gly 285 290 295 300 cag aca ctg cgg gct tcc atg cgt gag cta ggt ctc ctc atc ttc ttc 1444 Gln Thr Leu Arg Ala Ser Met Arg Glu Leu Gly Leu Leu Ile Phe Phe 305 310 315 ctc ttc att ggc gtg gtc ctc ttt tcc agc gca gtc tac ttt gct gaa 1492 Leu Phe Ile Gly Val Val Leu Phe Ser Ser Ala Val Tyr Phe Ala Glu 320 325 330 gtg gac cgg gtg gac acc cat ttc acc agc atc ccg gag tcc ttt tgg 1540 Val Asp Arg Val Asp Thr His Phe Thr Ser Ile Pro Glu Ser Phe Trp 335 340 345 tgg gca gtg gtc acc atg acc acg gtt ggc tat ggg gac atg gca ccc 1588 Trp Ala Val Val Thr Met Thr Thr Val Gly Tyr Gly Asp Met Ala Pro 350 355 360 gtc acc gtg ggt ggc aag atc gtg ggc tct ctg tgt gcc att gca ggt 1636 Val Thr Val Gly Gly Lys Ile Val Gly Ser Leu Cys Ala Ile Ala Gly 365 370 375 380 gtg ctc acc atc tct ctg cct gtg cct gtc att gtc tct aac ttt agc 1684 Val Leu Thr Ile Ser Leu Pro Val Pro Val Ile Val Ser Asn Phe Ser 385 390 395 tac ttt tac cac cgg gag aca gag ggc gaa gag gca ggg atg tac agc 1732 Tyr Phe Tyr His Arg Glu Thr Glu Gly Glu Glu Ala Gly Met Tyr Ser 400 405 410 cat gtg gac aca cag ccc tgc ggt acc ctg gag ggc aag gct aat ggg 1780 His Val Asp Thr Gln Pro Cys Gly Thr Leu Glu Gly Lys Ala Asn Gly 415 420 425 ggg ctg gtg gac tct gag gtg cct gaa ctc ctc cca cca ctc tgg ccc 1828 Gly Leu Val Asp Ser Glu Val Pro Glu Leu Leu Pro Pro Leu Trp Pro 430 435 440 cct gca ggg aaa cac atg gtg act gag gtg tga gggtcaactg gggtctccag 1881 Pro Ala Gly Lys His Met Val Thr Glu Val 445 450 ggagcagtgg ggtgggaggg aggagggaag gcaggtcagg tgctgggtta aggactaaga 1941 tggtaacaaa atcttaatct gaaggcatgt cacatggtgg cgggtacaga ttcctagggg 2001 gaccttatgt gacaggaatt gccaggattt gggttgtgtc cagggctccc cccattgatt 2061 gcgcaatgtg gtagagctgt gcaaatgtcc aggggctcta tgggtagcac tgtaagagac 2121 ttggccatag attgtgagtt tcctaggtgt tcgtggggtc ccactggggg caagtgtggt 2181 cccgttaaca cttgataggt actaatagaa ctttgggtcc tctagggcca agtcggctcc 2241 tgtaggtctc tggagcactg ttaaagagtg tgagcttgtg gctacatggt cacacacaga 2301 ggttatgtgg tgatacatag cagattgtgt ggattcatgt ttcttctagg actcaagtta 2361 ttttagattc tgtgagctct ggagtcatgc agacaggatg tgatcactct gggtcctgat 2421 ggaaaaaggg ttagggtata aaagatagac agaggcagag actcagataa agggacagag 2481 acacccccac acacacacac aacacacaat tctctgtgtt gtgcagggtt ataggactgg 2541 aatcatttta gggccatgca aagctgagat ggtgaccccc atgtgtctcc gaacagttga 2601 gtctgatgac ttctacggtc tcatgggact tgtgttactg tgagtcctgt ggaacttttg 2661 gttgaatttg actgtatgtg agggccattt taaacagtag atcagggtca cagcacagat 2721 aaaactaact acaagggagc aagcatgggc acgtggatgt gtgtggcccg ttgaacaagt 2781 ttactcaggg ttatgcattg tagagctggt agtgtctgta tctctgggtc cccctgcccg 2841 aagcacctag aaagacgatg ggaactagta acctgcctgt cttgctcatg tgggacccat 2901 atttctatgt tgtcccatgc tgtagtacaa agattcagag gctggttgga gccacaagga 2961 aagaaaacac agtagggcaa gagtaggtac ttgggaaaag atgtggcagg ggacagagat 3021 ctagaagaaa gaaagatgga gagaaggagc aggaggagca ggggaggggg aaagagggaa 3081 gggaaggagg gagagacaga gcaggtaaag aggaagagat gtgggggggg gggggagaag 3141 gacctggagc ccaagggtca tcctctctat tctctgagtc ataacagact ctaagctatg 3201 gcgtcagcat cccttagagc caaggaaggt caccacactc ctggaggtgc tctgtgtttc 3261 ctaggacaga aacccaaggc tgtagtgtgc tgtgcttcct caagttaccc agcggtcata 3321 gaccaagctg gtgccaggtg gcctgcctgt gacaccccca caacttctgg tgtgcaggta 3381 ttgcctgagg ccactggtcc tgtgtccttt gtttatccct taaaacaggg tccctctttg 3441 tagtgttggc tgtcctggaa ctcactacgt aga 3474 <210> SEQ ID NO 12 <211> LENGTH: 454 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 12 Met Glu Pro Arg Cys Pro Pro Pro Cys Gly Cys Cys Glu Arg Leu Val 1 5 10 15 Leu Asn Val Ala Gly Leu Arg Phe Glu Thr Arg Ala Arg Thr Leu Gly 20 25 30 Arg Phe Pro Asp Thr Leu Leu Gly Asp Pro Val Arg Arg Ser Arg Phe 35 40 45 Tyr Asp Gly Ala Arg Ala Glu Tyr Phe Phe Asp Arg His Arg Pro Ser 50 55 60 Phe Asp Ala Val Leu Tyr Tyr Tyr Gln Ser Gly Gly Arg Leu Arg Arg 65 70 75 80 Pro Ala His Val Pro Leu Asp Val Phe Leu Glu Glu Val Ser Phe Tyr 85 90 95 Gly Leu Gly Arg Arg Leu Ala Arg Leu Arg Glu Asp Glu Gly Cys Ala 100 105 110 Val Ala Glu Arg Pro Leu Pro Pro Pro Phe Ala Arg Gln Leu Trp Leu 115 120 125 Leu Phe Glu Phe Pro Glu Ser Ser Gln Ala Ala Arg Val Leu Ala Val 130 135 140 Val Ser Val Leu Val Ile Leu Val Ser Ile Val Val Phe Cys Leu Glu 145 150 155 160 Thr Leu Pro Asp Phe Arg Asp Asp Arg Asp Asp Pro Gly Leu Ala Pro 165 170 175 Val Ala Ala Ala Thr Gly Ser Phe Leu Ala Arg Leu Asn Gly Ser Ser 180 185 190 Pro Met Pro Gly Ala Pro Pro Arg Gln Pro Phe Asn Asp Pro Phe Phe 195 200 205 Val Val Glu Thr Leu Cys Ile Cys Trp Phe Ser Phe Glu Leu Leu Val 210 215 220 His Leu Val Ala Cys Pro Ser Lys Ala Val Phe Phe Lys Asn Val Met 225 230 235 240 Asn Leu Ile Asp Phe Val Ala Ile Leu Pro Tyr Phe Val Ala Leu Gly 245 250 255 Thr Glu Leu Ala Arg Gln Arg Gly Val Gly Gln Pro Ala Met Ser Leu 260 265 270 Ala Ile Leu Arg Val Ile Arg Leu Val Arg Val Phe Arg Ile Phe Lys 275 280 285 Leu Ser Arg His Ser Lys Gly Leu Gln Ile Leu Gly Gln Thr Leu Arg 290 295 300 Ala Ser Met Arg Glu Leu Gly Leu Leu Ile Phe Phe Leu Phe Ile Gly 305 310 315 320 Val Val Leu Phe Ser Ser Ala Val Tyr Phe Ala Glu Val Asp Arg Val 325 330 335 Asp Thr His Phe Thr Ser Ile Pro Glu Ser Phe Trp Trp Ala Val Val 340 345 350 Thr Met Thr Thr Val Gly Tyr Gly Asp Met Ala Pro Val Thr Val Gly 355 360 365 Gly Lys Ile Val Gly Ser Leu Cys Ala Ile Ala Gly Val Leu Thr Ile 370 375 380 Ser Leu Pro Val Pro Val Ile Val Ser Asn Phe Ser Tyr Phe Tyr His 385 390 395 400 Arg Glu Thr Glu Gly Glu Glu Ala Gly Met Tyr Ser His Val Asp Thr 405 410 415 Gln Pro Cys Gly Thr Leu Glu Gly Lys Ala Asn Gly Gly Leu Val Asp 420 425 430 Ser Glu Val Pro Glu Leu Leu Pro Pro Leu Trp Pro Pro Ala Gly Lys 435 440 445 His Met Val Thr Glu Val 450 <210> SEQ ID NO 13 <211> LENGTH: 1668 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME/KEY: promoter <222> LOCATION: (1288)..(1567) <221> NAME/KEY: misc_feature <222> LOCATION: (1666)..(1668) <223> OTHER INFORMATION: ORF start <221> NAME/KEY: misc_feature <222> LOCATION: (1310)..(1310) <223> OTHER INFORMATION: Potential transcription start <221> NAME/KEY: misc_feature <222> LOCATION: (102)..(246) <223> OTHER INFORMATION: Regulatory region <400> SEQUENCE: 13 aaaagaagag agaaggaatg gaaggaagga agacaggaag agaaagagtg ccaggattag 60 cagggcgttc gaacccttag tacctacctc tctccacacc cccagcagag ggcgaccagg 120 acttctttcc tgggagtctc agtgatcaaa cccctccact tcccccaagc ccatctgatg 180 gagctatttt tatgcagtgt caccggacac cagtggctag aaggccaccg tcttgtctct 240 gcgcccttca gttcctgaaa atgaccctgt ggcatctccc cggcccacac ccccaacccc 300 cgcccgttcc ggcaagacca gactcctttt gccagagtca tagccgcagc tcaggtcctg 360 ctaggtctca gaaagtcttg cgaagaatcc aggtggagac tctggagcga actctgggga 420 gagaatgggg cgtgtgtgca catgctcagt ggtttgcagc tgccagagtg accctaggat 480 gggacagcca ccgggactgt ggcagcaccc acatggagtg atggtcaggg agagatcaag 540 agatatgact ccggagaccc taagtcctct agagacccca aggggagacc caaaggggag 600 cggccgagga accctgagac agagacatgg agggctaaga gataatgagc aaaaagagac 660 ctagagagga gagacaaaga gaccaagaga gacaagagat aaacggagac agaccaagag 720 tcaaaataaa ggcggagacc gagacgtaga ggctggcaga gggacccata cagaggcccc 780 cagaacgacg aatctcagaa ataaatgacc catagagata ctcagagata catcccaaaa 840 gagacagaga cccagagggg acagccggac acagacacac aagagagtga gagacaaagg 900 tgcaaacagg gcgactccag gccgggcgcc gtggctcacg cttgtaaccc cagcaattcg 960 ggaggccaag gagggcagat cacttgaggt cgggagtacc agacctgcct ggccaacatg 1020 gtgaaacccc ttctcaacta aaaaagaaaa aagaaaaaaa attagctggg cttggtggcg 1080 cctgtaattc cagctactag ggaggctgag gcacgagaat cgcttgatcc cgggaggtgg 1140 aggttgttgc agtgagccga gatcgcgcca ctgcactcca gcccgggcga cagagggaaa 1200 ctgtgtctca aaaaaaaaaa aaaaaaaaaa gacagaaaga aagaagaaag agaaaagaaa 1260 agaggcgact gcaactgaag cctgattctg acgaaacaca cgcacacgga aacttggaga 1320 gacgcaggac aggatcccgg cggcagaagg acggagagaa aggggacccc gggacgggaa 1380 aggcgcagag caggcgcggg cggcggcggc ggcggggcag ggcagggcgg gcgtcccggc 1440 agagggcgcg cggtcgccct gtcgccctcc gccccgccgg ggtcacagtg ccccctccct 1500 cgcgccctag ccgccctgcc gggctatttt tacgcgcgga caccggacac cggacaccgg 1560 gctggggcgg cggcggcggc ggccgaggcg gccgaggcgg ggccgcaccg gggccgggcg 1620 tcggggccac acgtcggttc gcgggtcgcc ggggctgcgc gcgccatg 1668 

1. An isolated nucleic acid molecule selected from: (a) nucleic acid molecules comprising a nucleotide sequence as shown in SEQ ID NO:1 or 11: (b) nucleic acid molecules comprising a nucleotide sequence capable of hybridizing, under stringent hybridization conditions, to a nucleotide sequence complementary the polypeptide coding region of a nucleic acid molecule as defined in (a) and which codes for a biologically active KCNA7 polypeptide or a functionally equivalent modified form thereof; and (c) nucleic acid molecules comprising a nucleic acid sequence which is degenerate as a result of the genetic code to a nucleotide sequence as defined in (a) or (b) and which codes for a KCNA7 polypeptide or a functionally equivalent modified form thereof.
 2. An isolated mammalian KCNA7 polypeptide encoded by the nucleic acid according to claim
 1. 3. An isolated human KCNA7 polypeptide having an amino acid sequence shown as SEQ ID NO:2 in the sequence listing.
 4. An isolated murine kcna7 polypeptide having an amino acid sequence shown as SEQ ID NO:12 in the sequence listing.
 5. A vector harboring the nucleic acid molecule according to claim
 1. 6. A replicable expression vector, which carries and is capable of mediating the expression of a nucleic acid molecule according to claim
 1. 7. A cultured host cell harboring a vector according to claim 5 or
 6. 8. A process for production of a mammalian KCNA7 polypeptide which comprises culturing a host cell according to claim 7 under conditions whereby said polypeptide is produced, and recovering said polypeptide.
 9. A method for identifying an agent modulating voltage-gated potassium ion channel activity, comprising (i) providing a cell expressing the mammalian KCNA7 polypeptide according to any one of claims 2 to 4; (ii) contacting said cell with a candidate agent; and (iii) monitoring said cell for an effect Stat is not present in the absence of said candidate agent.
 10. A method for identifying an agent modulating the expression of a mammalian KCNA7 nucleic acid molecule, said method comprising the steps (i) contacting a candidate agent with a nucleic acid molecule according to claim 1; and (ii) determining whether said candidate agent modulates the expression of the said nucleic acid molecule.
 11. A method for identifying an agent useful for the treatment of diabetes, said method comprising the steps (i) contacting a candidate agent with a nucleic acid molecule according to claim 1; and (ii) determining whether said candidate agent decreases or inhibits the expression of the nucleic acid molecule, such decrease or inhibition being indicative for a compound useful for the treatment of diabetes.
 12. A method for identifying an agent useful for the treatment of ion channel related conditions selected from the group consisting of schizophrenia, depression, anxiety, attention deficit hyperactivity disorder, migraine, stroke, ischemia, glaucoma, macular degeneration, epilepsy, and neurodegenerative disease, said method comprising the steps (i) contacting a candidate agent with a nucleic acid molecule according to claim 1; (ii) determining whether said candidate agent modulates the expression of the nucleic acid molecule, such modulation being indicative for a compound useful for the treatment of said ion channel related conditions.
 13. A method for identifying an agent modulating the biological activities of a mammalian voltage-gated potassium ion channel, said method comprising the steps (i) contacting a candidate agent with the mammalian CNA7 polypeptide according to any one of claims 2 to 4; and (ii) determining whether said candidate agent modulates the biological activities of the said polypeptide.
 14. A method for identifying an agent useful for the treatment of diabetes, said method comprising the steps (i) contacting a candidate agent with a mammalian KCNA7 polypeptide according to any one of claims 2 to 4; and (ii) determining whether said candidate agent decreases or inhibits the biological activities of the said mammalian KCNA7 polypeptide, such decrease or inhibition being indicative for a compound useful for the treatment of diabetes.
 15. A method for identifying an agent useful for the treatment of ion channel related conditions selected from the group consisting of schizophrenia, depression, anxiety attention deficit hyperactivity disorder, migraine, stroke, ischemia, glaucoma, macular degeneration, epilepsy, and neurodegenerative disease, said method comprising the steps (i) contacting a candidate agent with a mammalian KCNA7 polypeptide according to any one of claims 2 to 4; and (ii) determining whether said candidate agent modulates the biological activities of the said mammalian KCNA7 polypeptide, such modulation being indicative for a compound useful for the treatment of said ion channel related conditions.
 16. A method for the identification of an agent modulating transcription of the human KCNA7 gene, comprising determining whether a candidate agent modulates expression of the human KCNA7 gene via a mechanism dependent upon a regulatory region shown as positions 105 to 114 or 201 to 211 in SEQ ID NO:13. A method for the identification of an agent modulating transcription of the human KCNA7 gene said method comprising the steps (i) contacting a candidate agent with a regulatory region shown as positions 105 to 114 or 201 to 211 in SEQ ID NO:13; and (ii) determining whether said candidate agent modulates expression of the human KCNA7 gene, such modulation being indicative for an agent modulating transcription of the human KCNA7 gene. 